Exercise enhances vaccine-induced antigen-specific T cell responses. Regular moderate exercise has been proposed to enhance immune function, but its effects on immunity and their consequences have not been well studied. Mice without (AL) or with access (AL + EX) to voluntary running wheels were vaccinated with a model antigen (ovalbumin (OVA)) via intranasal or subcutaneous routes to target the mucosal and systemic immune compartments, respectively. EX-enhanced OVA-specific CD4+ T cell cytokine production and proliferation in all lymphoid organs examined without changes in cell distribution in any organ. These results suggest that coupling moderate exercise with vaccination may enhance vaccine efficacy for the prevention and/or therapy of numerous diseases. In another study, energy restriction and exercise differentially enhance components of systemic and mucosal immunity in mice. The prevalence of obesity, an established risk factor for several chronic diseases including cancer, has risen dramatically over the past four decades. Dietary change and/or increased physical activity are the most commonly recommended lifestyle-based strategies for preventing or reversing obesity. One of several physiological systems that may be enhanced by dietary change and exercise is the immune system. This project examines the effects of energy restriction (ER;30% reduction relative to control energy intake) and/or EX (voluntary-wheel running) on systemic and mucosal immune function. Female C57BL/6 mice were randomized into four treatment conditions: 1) controls consuming food ad libitum (AL);2) AL with access to running wheels (AL+EX);3) 30% ER;and 4) 30% ER with access to running wheels (ER+EX). Both ER and EX reduced spleen weight and the number of splenic T and B lymphocytes (P&lt;0.05). ER enhanced NK cell function, but significantly reduced Con A-induced T cell proliferation (P&lt;0.05). In contrast, EX significantly enhanced Con A-induced proliferation and cytokine production from Peyers patch cells (P&lt;0.05). These data suggest that ER and EX enhance some, but not all components of the immune system, and are likely working via different biological mechanisms to regulate NK and T cell function.